Protective role of clusterin/apolipoprotein j against neointimal hyperplasia via antiproliferative effect on vascular smooth muscle cells and cytoprotective effect on endothelial cells

Han Jong Kim, Eun Kyung Yoo, Joon Young Kim, Young Keun Choi, Hyo Jeong Lee, Jeong Kook Kim, Nam Ho Jeoung, Ki Up Lee, In Sun Park, Bon Hong Min, Keun Gyu Park, Chul Ho Lee, Bruce J. Aronow, Masataka Sata, In Kyu Lee

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

Abstract

OBJECTIVE-: Clusterin is induced in vascular smooth muscle cells (VSMCs) during atherosclerosis and injury-induced neointimal hyperplasia. However, its functional roles in VSMCs and endothelial cells remain controversial and elusive. This study was undertaken to clarify the role of clusterin in neointimal hyperplasia and elucidate its mechanism of action. METHODS AND RESULTS-: Adenovirus-mediated overexpression of clusterin (Ad-Clu) repressed TNF-α-stimulated expression of MCP-1, fractalkine, ICAM-1, VCAM-1, and MMP-9, leading to inhibition of VSMC migration. Both Ad-Clu and secreted clusterin suppressed VSMC proliferation by inhibiting DNA synthesis, but not by inducing apoptosis. Ad-Clu upregulated p53 and p21 but downregulated cyclins D and E, leading to suppression of pRb phosphorylation and subsequent induction of G1 arrest in VSMCs. Clusterin deficiency augmented VSMC proliferation in vitro and accelerated neointimal hyperplasia in vivo, but concomitantly impaired reendothelialization in wire-injured murine femoral arteries. Moreover, Ad-Clu significantly reduced neointimal thickening in balloon-injured rat carotid arteries. Clusterin also diminished TNF-α-induced apoptosis of human umbilical vein endothelial cells and restored endothelial nitric oxide synthase expression suppressed by TNF-α. CONCLUSION-: These results suggest that upregulation of clusterin during vascular injury may be a protective response against, rather than a causative response to, the development of neointimal hyperplasia.

Original languageEnglish
Pages (from-to)1558-1564
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume29
Issue number10
DOIs
Publication statusPublished - 2009 Oct

Keywords

  • Clusterin
  • Endothelial cells
  • Neointimal hyperplasia
  • Proliferation
  • VSMC

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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